Endothelin-1 stimulates contraction of rat glomerular mesangial cells and potentiates beta-adrenergic-mediated cyclic adenosine monophosphate accumulation.

Abstract

The newly isolated peptide, endothelin-1 (ET-1), is a potent pressor agent that reduces GFR and the glomerular ultrafiltration coefficient. Recent evidence demonstrates that ET-1 mobilizes intracellular Ca2" (ICa2+Ii) in glomerular mesangial cells by activating the phosphoinositide cascade. The present experiments were designed to examine whether ET-1 stimulates mesangial cell contraction and regulates the synthesis of PGE2 and cAMP, which dampen vasoconstrictor-induced mesangial contraction. ET-1 (2 1 nM) reduced the cross-sectional area of rat mesangial cells cultured on three-dimensional gels of collagen type I. ET-1 also caused complex rearrangements of F-actin microfilaments consistent with a motile response. Contraction in response to ET-1 occurred only at concentrations that activate phospholipase C, and contraction was unaffected by blockade of dihydropyridine-sensitive C(a2+ channels.Elevation of [Ca2J11 with ionomycin, to equivalent concentrations of [Ca2I1i achieved with ET-1, also reduced mesangial cell cross-sectional area. ET-1 (0.1 isM) also evoked IH]arachidonate release and a fivefold increase in PGE2 synthesis as well as increased synthesis of PGF2. and small changes of TXB2. ET-1 caused a minor increase in intracellular cAMP accumulation only in the presence of 3-isobutyl-1-methylxanthine. ET-1 also amplified cAMP production in response to isoproterenol. TPA and ionomycin, alone and in combination, failed to mimic the potentiating effect of ET-1; however, indomethacin blocked ET-1-induced potentiation of isoproterenolstimulated cAMP, which was restored by addition of exogenous 10 nM PGE2. Thus the present data demonstrate that ET-1 stimulates mesangial cell contraction via pharmacomechanical coupling and activates phospholipase A2 to produce PGE2, PGFu, and TXB2. ET-1 also amplified ft adrenergicstimulated cAMP accumulation by a PGE2-dependent mechanism. (J. Clin. Invest. 1990. 85:790-797.)

Changes of endothelin in streptozotocin-induced diabetic rats: effects of an angiotensin converting enzyme inhibitor, enalapril maleate

“…This change may be due to ET-1 in the renal cells because ET-1 exists not only in the vascular endothelial cells but also in the mesangial cells or tubular cells (Kosaka et al 1989, Simonson & Dunn 1990, Kohan 1991. Fukui et al (1994) reported that increases in ET-1 mRNA (2, 3 kilobases (kb)) in isolated glomeruli from diabetic rat kidney were partly reversed by enalapril treatment.…”

Endothelin action in rat liver. Receptors, free Ca2+ oscillations, and activation of glycogenolysis.

“…Glycogen (32), kidney (27), vascular smooth muscle cells (33,23), and adrenal glomerulosa cells (22), and could explain the potent long lasting effect of this peptide (1,6). Elevation of intracellular free Ca2+ and not of cAMP has been invoked to mediate the action of ET-1; only in mesangial cells (34) and Swiss 3T3 fibroblasts (35) has a small increase (34) or decrease (35) in cAMP levels been reported in response to ET-1. Our results clearly show that ET-1 does not affect cAMP levels in rat hepatocytes (Table I), but provokes oscillations in cytosolic free Ca2" in single aequorin-injected hepatocytes, similar to that produced by other Ca2+ mobilizing hormones (1 1, 19).…”

Identification of a contractile function for renal medullary interstitial cells.

“…RMIC were stained using previously described methodology (19). Briefly, cells were incubated in KRB alone or containing 10 nM ET-1 or 10 nM AVP for 30 min at 37°C.…”